1. Field of the Invention
The present invention relates to monoclonal antibodies which bind specifically to the extracellular domain of the SIRP cell surface glycoproteins.
2. Related Prior Art
Signal regulator proteins (termed SIRP in that which follows) are cell surface glycoproteins which are expressed on myeloid and neuronal cells; see WO 97/48723 and Kharitonenkov et al.: A family of proteins that inhibit signalling through tyrosine kinase receptors, in Nature, volume 386, March 1997, pages 181-186.
According to the abovementioned publications, the SIRPs are involved in the negative regulation of receptor tyrosine kinase-coupled signal pathways. The SIRP family contains at least 15 members, which fall into two subfamilies. All the SIRP proteins possess an immunoglobulin-like extracellular domain, which is frequently present in receptors, and a transmembrane domain. The two subfamilies differ with regard to the presence or absence of a cytoplasmic domain which is able to bind SH-2 domains. The subfamily which is termed SIRP4 in WO 97/48723 and SIRPα in the publication by Kharitonenkov et al. possesses such a cytoplasmic domain, while the subfamily which is termed SIRP1 in WO 97/48723 and SIRPβ in the article by Kharitonenkov et al. does not possess this domain.
Cellular signal transmission is a fundamental mechanism by which external stimulations, which regulate various cellular processes, are transmitted into the interior of cells. A central biochemical mechanism in signal transmission involves the reversible phosphorylation of proteins, as a result of which the activity of mature proteins is regulated by their structure and function being altered. This process involves, on the one hand, protein phosphatases, which cleave phosphoryl groups from substrate proteins by hydrolysis which phosphoryl groups on the other hand are transferred to the substrate proteins by protein kinases. The oppositely directed functions of protein kinases and protein phosphatases regulate the signal flow in the signal transmission processes.
The protein tyrosine kinases of the receptor type constitute one group of the kinases which are involved in the reversible phosphorylation.
Tyrosine phosphatases are able to downregulate the catalytic activity of protein kinases which are involved in cell proliferation and are therefore regarded as being possible antitumour proteins. In addition to this, it is assumed that protein phosphatases are also involved in cellular differentiation processes. The best characterized member of the human SIRP family, SIRPα (or else SIRP4), is a substrate of activated receptor tyrosine kinases. Overexpression of SIRPα leads to the reaction to the receptor tyrosine kinase ligands EGF (epidermal growth factor), insulin and PDGF (platelet-derived growth factor) being reduced.
It consequently follows, from the two abovementioned documents, that SIRP acts as a negative regulator in the proliferation and differentiation of cells, which means that antibodies directed against SIRP can play a role not only when investigating the expression and function of SIRP but also in therapeutic and diagnostic applications in connection with diseases or disturbances in which there is an irregularity in a signal transmission pathway.
In this connection, WO 97/48723 describes, in a general manner, a method for producing monoclonal antibodies which are directed against SIRP polypeptides, with this publication additionally mentioning the therapeutic/diagnostic use of such antibodies, in particular in connection with immunological test methods. However, this document does not present any actual monoclonal antibodies and does not refer, in particular, to any deposition in accordance with the Budapest Treaty.